Review
Biochemistry & Molecular Biology
Amit Meir, Kevin Mace, Yogesh Vegunta, Sunanda M. Williams, Gabriel Waksman
Summary: This review provides an update on recent advances in substrate recruitment and delivery by recruitment platforms associated with Type III, IV, and VI secretion systems in gram-negative bacteria.
TRENDS IN MICROBIOLOGY
(2023)
Article
Microbiology
Miguel Diaz-Guerrero, Meztlli O. Gaytan, Eduardo Soto, Norma Espinosa, Elizabeth Garcia-Gomez, Arely Marcos-Vilchis, Angel Andrade, Bertha Gonzalez-Pedrajo
Summary: The type III secretion system (T3SS) is a complex molecular device that enables pathogenic bacteria to transport effector proteins directly into host cells. The CesL/SepL/SepD complex regulates the switch from translocator to effector secretion in enteropathogenic Escherichia coli, ensuring proper secretion and stability of the components involved. CesL also interacts with the cytoplasmic domains of export gate components, contributing to the regulation of substrate secretion.
Article
Gastroenterology & Hepatology
Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini
Summary: This study reveals that loss of PI3K-C2 gamma in pancreatic ductal adenocarcinoma (PDAC) leads to hyperactivation of mTORC1 pathway and rewiring of glutamine metabolism, increasing tumor aggressiveness. Furthermore, PI3K-C2 gamma knockout tumors fail to adapt to metabolic stress induced by glutamine depletion, resulting in cell death. These findings suggest that targeting mTORC1 and glutamine metabolism may be a potential strategy for personalized treatment in PDAC with PI3K-C2 gamma loss.
Article
Plant Sciences
Naama Wagner, Michael Alburquerque, Noa Ecker, Edo Dotan, Ben Zerah, Michelle Mendonca Pena, Neha Potnis, Tal Pupko
Summary: In this study, novel machine-learning algorithms were developed to characterize the secretion signal of Type III effectors in both plant and animal pathogens. A benchmark dataset was curated and the results showed that the novel approach had substantially better classification accuracy compared to previous methodologies. The study also revealed that plant and animal pathogen effectors may have different secretion signals.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Microbiology
Merel P. M. Damen, Aniek S. Meijers, Esther M. Keizer, Sander R. Piersma, Connie R. Jimenez, Coenraad P. Kuijl, Wilbert Bitter, Edith N. G. Houben
Summary: Pathogenic mycobacteria utilize the ESX-1 secretion system to mediate intracellular survival, but determining the responsible ESX-1 substrate is challenging due to complex secretion dependencies. This study reveals the critical role of the ESX-1 substrate PPE68 in mediating the secretion of ESX-1 substrates in Mycobacterium marinum, providing insights into the functional understanding of T7SSs and the virulence of Mycobacterium tuberculosis.
Article
Immunology
Sebastien Triboulet, Maimouna D. N'Gadjaga, Beatrice Niragire, Stephan Koestlbacher, Matthias Horn, Vishukumar Aimanianda, Agathe Subtil
Summary: The obligate intracellular bacteria Chlamydia trachomatis store glycogen in the vacuoles and convert Glc1P to Glc6P through bacterial PGM. Glycogen accumulation in the vacuoles of certain Chlamydia species is correlated with the presence of T3S signals in CT295 orthologs.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Min Jiang, Youze Zhang, Peng Li, Jinjing Jian, Changling Zhao, Guosong Wen
Summary: This review summarizes the research progress in recent years on the classification and functions of MAPK cascades in plants, with a focus on the research status and general methods available for identifying MAPK substrates, and provides suggestions for future research directions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jie Yang, Weibin Gong, Si Wu, Hong Zhang, Sarah Perrett
Summary: Hsp70 proteins are ancient chaperones with important roles in cellular processes, making them potential drug targets for diseases like cancer. The inhibitor PES has been shown to interact with specific residues in Hsp70, affecting its structure and function similarly to glutathionylation. This study provides insights into developing covalent inhibitors for Hsp70.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Microbiology
Joanna E. Musik, Jessica Poole, Christopher J. Day, Thomas Haselhorst, Freda E. -C. Jen, Thomas Ve, Veronika Masic, Michael P. Jennings, Yaramah M. Zalucki
Summary: This study designed 11 peptides to mimic signal peptides that are inefficiently cleaved by LepB. The binding affinity and inhibitory potential of these peptides against LepB were assessed. It was found that the tryptophan residue in the signal peptide inhibited the cleavage of the peptide by LepB, and replacing this residue with alanine improved the cleavage efficiency.
MICROBIOLOGY SPECTRUM
(2023)
Article
Chemistry, Multidisciplinary
Helal Abujubara, Jordi C. J. Hintzen, Shadi Rahimi, Ivan Mijakovic, Daniel Tietze, Alesia A. Tietze
Summary: The bacterial enzyme Sortase A (SrtA) plays a crucial role in the virulence and infection establishment of Gram-positive pathogenic bacteria. However, the development of potent inhibitors for Sortase A remains a challenge. In this study, we synthesized a series of peptidomimetic inhibitors based on the sorting signal recognized by Sortase A and identified several promising inhibitors with strong inhibitory activity. Furthermore, we discovered that some of these inhibitors showed an effect on the growth and biofilm inhibition of pathogenic Staphylococcus aureus, suggesting their potential as future drug leads.
Article
Endocrinology & Metabolism
Lifang Xie, Wanling Lu, Yanhan Zhang, Lu Deng, Ming Liu, Hong Gao, Chunguang Xie, Gang Wang
Summary: A glucose-activated single-strand insulin analog switch system has been developed in this study, which can achieve repeatable secretion of insulin analog in response to hyperglycemia, leading to long-term precise control of blood glucose. This system offers sufficient biosafety and shows potential for the treatment of type 1 diabetes.
Article
Biochemistry & Molecular Biology
Jyoti M. Gurung, Ayad A. A. Amer, Shiyun Chen, Andreas Diepold, Matthew S. Francis
Summary: YscX, an important component of the Yersinia type III secretion system, remains poorly understood in terms of its function and mode of action. This study identified an N-terminal secretion domain in YscX that promotes its own secretion and contains essential information for its function. The secretion permissiveness of YscX is closely related to the assembly of an operational secretion system.
MOLECULAR MICROBIOLOGY
(2022)
Article
Biochemical Research Methods
Wei Wang, Wayne A. Hendrickson
Summary: Hsp70 molecular chaperones play a crucial role in protein disaggregation and folding by binding to ATP and client peptides, with a balance between restraining and stimulating states. New insights have been gained into the Hsp70 chaperone cycle through the discovery of intermediate states and structural plasticity that affect binding interactions.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Xuzi Cai, Kang-Nan Wang, Wen Ma, Yuanyuan Yang, Gui Chen, Huijiao Fu, Chunhui Cui, Zhiqiang Yu, Xuefeng Wang
Summary: The newly designed Ir-NPs showed high tumor-targeting ability, excellent antitumor effect, and low toxicity, making them a promising candidate for clinical applications in bioimaging and PDT. Additionally, they also demonstrated potential as a two-photon imaging agent for deep tissue bioimaging.
JOURNAL OF NANOBIOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Alina Guse, Manuel Halte, Svenja Huesing, Marc Erhardt
Summary: The study revealed that the type-III secretion system of bacterial flagellum has a remarkable substrate specificity during flagellar assembly, accurately secreting the required substrates at different stages, and the specificity switch is unidirectional and irreversible.
MOLECULAR MICROBIOLOGY
(2021)
Article
Chemistry, Organic
Brandon M. Young, Paolo Rossi, P. Jake Slavish, Yixin Cui, Munia Sowaileh, Jitendra Das, Charalampos G. Kalodimos, Zoran Rankovic
Summary: Isotopically labeled amino acids are commonly used for studying protein structure and dynamics by NMR. This study presents a facile gram-scale synthesis of compounds 1b and 2b under standard laboratory conditions from a common intermediate. The improved signal intensity with lower amounts of labeled precursor makes 1b and 2b potential alternatives to current labeling approaches.
Editorial Material
Multidisciplinary Sciences
Jochem H. Smit, Guillaume Roussel, Anastassios Economou
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Analytical
Juergen Claesen, Srinath Krishnamurthy, Andy M. Lau, Anastassios Economou
Summary: This study introduces a method of using a linear model combined with an empirical Bayes approach to detect differentially deuterated peptides, in order to study the structure and dynamics of protein states. By moderating the two-sample t-tests and F-statistic, the number of false positive and false negative findings can be reduced.
ANALYTICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Nicolas Rosa, Hristina Ivanova, Larry E. Wagner, Justin Kale, Rita La Rovere, Kirsten Welkenhuyzen, Nikolaos Louros, Spyridoula Karamanou, Victoria Shabardina, Irma Lemmens, Elien Vandermarliere, Kozo Hamada, Hideaki Ando, Frederic Rousseau, Joost Schymkowitz, Jan Tavernier, Katsuhiko Mikoshiba, Anastassios Economou, David W. Andrews, Jan B. Parys, David Yule, Geert Bultynck
Summary: The study shows that Bcl-xL and Bcl-2 have similar anti-apoptotic effects in controlling endoplasmic reticulum Ca2+ release, challenging the current understanding of their divergent functions in Ca2+ signaling modulation.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biochemistry & Molecular Biology
Tao Xie, Tamjeed Saleh, Paolo Rossi, Darcie Miller, Charalampos G. Kalodimos
Summary: Imatinib binds to an allosteric pocket on Abl, promoting kinase activity and providing a mechanism for drug resistance in Abl variants with imatinib-resistant mutations in the catalytic site. Combining imatinib with allosteric inhibitors maximizes their inhibitory effect on Bcr-Abl.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Biao Yuan, Athina G. Portaliou, Rinky Parakra, Jochem H. Smit, Jiri Wald, Yichen Li, Bindu Srinivasu, Maria S. Loos, Harveer Singh Dhupar, Dirk Fahrenkamp, Charalampos G. Kalodimos, Franck Duong van Hoa, Thorben Cordes, Spyridoula Karamanou, Thomas C. Marlovits, Anastassios Economou
Summary: Type III protein secretion is common in Gram-negative pathogens, with SctV forming peripheral oligomeric clusters in EPEC and serving as a key receptor for different chaperone/exported protein pairs. The dynamic motions of SctV protomers, modulated by chaperones and ATPase, may allosterically affect the secretion process.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mary C. Clay, Tamjeed Saleh, Samuel Kamatham, Paolo Rossi, Charalampos G. Kalodimos
Summary: Methyl-TROSY spectroscopy has expanded the application of solution-state NMR to study supra-molecular machineries. Accurate methyl chemical shift assignment remains a challenge. This work presents the current technology for methyl labeling, data collection, data analysis, and automated methyl assignment approaches, along with Python extensions and a standalone network analysis program for the task.
Article
Cell Biology
Srinath Krishnamurthy, Marios-Frantzeskos Sardis, Nikolaos Eleftheriadis, Katerina E. Chatzi, Jochem H. Smit, Konstantina Karathanou, Giorgos Gouridis, Athina G. Portaliou, Ana-Nicoleta Bondar, Spyridoula Karamanou, Anastassios Economou
Summary: Protein machines undergo conformational motions to interact with and manipulate polymeric substrates. The intrinsic dynamics of Sec translocase ATPase, SecA, and the binding of preproteins combine to achieve translocation. This universal mechanism allows any preprotein to undergo translocation and be secreted.
Article
Multidisciplinary Sciences
Brahm J. Yachnin, Laura R. Azouz, Ralph E. White, Conceicao A. S. A. Minetti, David P. Remeta, Victor M. Tan, Justin M. Drake, Sagar D. Khare
Summary: In this study, a computational design, screening, and sequencing-based approach for proenzyme design was developed to confine the activity of a protein to a specific microenvironment. By studying a model system, it was found that the most effectively designed variants showed 80% inhibition compared to the unmodified protein, and their activity could be fully restored by proteolysis. Introducing disulfide bonds increased the degree of inhibition to 98% but decreased the degree of restoration of activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Dries Smets, Jochem Smit, Ying Xu, Spyridoula Karamanou, Anastassios Economou
Summary: Signal peptides delay folding by crosstalking with mature domains, altering the folding landscape of proteins.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biology
Conceicao A. Minetti, David P. Remeta, Keiji Hashimoto, Radha Bonala, Rajesh Chennamshetti, Xingyu Yin, Miguel Garcia-Diaz, Arthur P. Grollman, Francis Johnson, Viktoriya S. Sidorenko
Summary: In this study, synthetic analogs of aurintricarboxylic acid (ATA) were designed and evaluated for their interactions with human serum albumin, yeast ribosomes, and SARS-CoV-2 RNA-dependent RNA polymerase. Promising lead compounds were selected based on their binding energetics and functional activities in inhibiting RNA replication and protein synthesis.
Article
Biochemistry & Molecular Biology
Dries Smets, Alexandra Tsirigotaki, Jochem H. Smit, Srinath Krishnamurthy, Athina G. Portaliou, Anastassia Vorobieva, Wim Vranken, Spyridoula Karamanou, Anastassios Economou
Summary: This study investigates the delayed folding mechanism and the regulatory role of signal peptides in the Sec pathway. By comparing two homologous proteins, PpiA and PpiB, it is found that PpiA folds slower and the folding process involves hierarchical foldons. The folding of PpiA is delayed by less hydrophobic native contacts, frustrated residues, and a beta-turn in the earliest foldon, as well as by signal peptide-mediated disruption of foldon hierarchy. Additionally, grafting selected residues or the signal peptide of PpiA onto PpiB converts it into a slow folder with enhanced in vivo secretion. These structural adaptations facilitate protein trafficking.
Review
Biology
Conceicao A. Minetti, David P. Remeta
Summary: Drug discovery strategies aim to identify selective "magic bullet" drugs to address various emerging and existing health threats. The design, development, and optimization of drugs require the evaluation of specific criteria and properties from different disciplines. Thermodynamics plays a crucial role in drug discovery by elucidating the selectivity and specificity of drug-target interactions.
